Abstract

Telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in numerous observational studies, but association results have been inconsistent. These findings may have been affected by several limitations, including bias from reverse causation, reliance on a single blood specimen, residual confounding or measurement outside of the etiologically relevant time period. Germline genetic variations associated with leukocyte telomere length are not affected by an individual’s exposure to confounders and may act as unconfounded markers of the relationship between telomere length and RCC risk. We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk. Genotypes from nine telomere length associated variants were aggregated for 10,785 RCC cases and 21,579 cancer-free controls. We found that the number of telomere length variants associated with RCC risk (P-value<0.05) was significantly higher than what would be expected by chance (5/9 variants, binomial P-value=3.32×10−5). We aggregated the telomere length associated variants into a weighted genetic risk score (GRS), where one GRS unit equals to an inferred one Kb change in telomere length. Genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07, 95% CI=1.70-2.52, P-value=7.14×10−13). This association was consistent across increasing deciles of telomere length GRS (Trend P-value=5.58×10−12). As a sensitivity analysis, we removed two telomere length variants in linkage disequilibrium with RCC genome-wide associated regions (rs10936599 and rs9420907) from the telomere length GRS, the association with RCC risk remained statistically significant (OR=1.73, 95% CI=1.35-2.20, P-value=1.07×10−5). When performing analyses by RCC subtype (clear cell=5,574 cases, papillary=573 cases and chromophobe=203 cases), all subtypes investigated showed positive GRS effect estimates, suggesting higher risk for longer telomeres, however, due to limited sample sizes the estimates were only significant for clear cell (OR=1.93, 95% CI=1.50-2.49, P-value=3.79×10−7) and papillary subtypes (OR=1.96, 95% CI=1.01-3.81, P-value=0.046). In conclusion, our results suggest a genetic background that favors longer telomeres is associated with increased RCC risk.